Renin is a natural enzyme which is released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing decapeptide, angiotensin I. This is in turn cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renins have been sought as an agent for control of hypertension, congestive heart failure, and hyperaldosteronism.
The present invention concerns novel peptides which inhibit renin. It also concerns pharmaceutical compositions containing these novel peptides, methods of treating renin-associated hypertension, congestive heart failure, hyperaldosteronism, glaucoma, and diseases caused by retroviruses including HTLV-I, -II, and -III, as well as the use of the peptides as diagnostic tools, and the methods for preparing the peptides.
U.S. Pat. No. 4,725,584 covers 1-peptidyl 1-amino 2,4-diols of formula ##STR1## wherein A is an N-protecting group, R.sub.1 is arylmethyl, R.sub.2 is alkyl of one to six carbons or imidazolyemethyl, R.sub.3 is cycloalkylalkyl, and R.sub.4 alkyl, alkylmercapto or alkylsulphonyl wherein each alkyl can be from one to six carbons.
European Application Publication No. 202,577 discloses certain N(acyldipeptidyl)-aminoglycols of formula ##STR2## wherein R.sub.1 is alkoxy containing one to six carbon atoms or lower alkyl containing one to six carbon atoms; R.sub.2 is benzyl or napthylmethyl, R.sub.3 is lower alkyl containing one to six carbon atoms or imidazolemethyl; R.sub.4 is benzyl, R.sub.5 is hydrogen or lower alkyl and n is 0 or 1.
R. Metternich and W. Liidi, Tet. Lett 29, 3923-6 (1988) discloses an aldol approach starting directly from a pyruvate enol and reacting it chelate-controlled with the chiral .alpha.-aminoaldehyde thus obtaining the aldol adduct and converting this by 1,3-induced asymmetric hydrogenation into chiral .gamma.-(aminoalkyl)-.alpha.-hydroxy-.gamma. lactones which are used in the synthesis of renin inhibitors.
Structurally the positions of the various amino acids of the compounds of the instant invention may be designated by reference to the octapeptide which is the minimal angiotensinogen sequence cleaved by renin, namely: ##STR3##
A designation for the compounds of this invention is illustrated below. The diaminodiol is considered to occupy the P.sub.1 -P.sub.2 ' positions. For example ##STR4##